Tyrosine kinases are receptor type or non-receptor type proteins, which transfer the terminal phosphate of ATP to tyrosine residues of proteins thereby activating or inactivating signal transduction pathways. These proteins are known to be involved in many cellular mechanisms, which in case of disruption, lead to disorders such as abnormal cell proliferation and migration as well as inflammation.
As of today, there are about 58 known receptor tyrosine kinases. Included are the well-known VEGF receptors (Kim et al., Nature 362, pp. 841-844, 1993), PDGF receptors, c-kit, Flt-3 and the FLK family. These receptors can transmit signals to other tyrosine kinases including Src, Raf, Frk, Btk, Csk, Abl, Fes/Fps, Fak, Jak, Ack, etc.
Among tyrosine kinase receptors, c-kit is of special interest. Indeed, c-kit is a key receptor activating mast cells, which have proved to be directly or indirectly implicated in numerous pathologies for which the Applicant filed WO 03/004007, WO 03/004006, WO 03/003006, WO 03/003004, WO 03/002114, WO 03/002109, WO 03/002108, WO 03/002107, WO 03/002106, WO 03/002105, WO 03/039550, WO 03/035050, WO 03/035049, WO 03/0720090, WO 03/072106, WO 04/076693 and WO 2005/016323.
We found that mast cells present in tissues of patients are implicated in or contribute to the genesis of diseases such as autoimmune diseases (rheumatoid arthritis, inflammatory bowel diseases (IBD)) allergic diseases, bone loss, cancers such as solid tumors, leukaemia and GIST, tumor angiogenesis, inflammatory diseases, interstitial cystitis, mastocytosis, graft-versus-host diseases, infection diseases, metabolic disorders, fibrosis, diabetes and CNS diseases. In these diseases, it has been shown that mast cells participate in the destruction of tissues by releasing a cocktail of different proteases and mediators such as histamine, neutral proteases, lipid-derived mediators (prostaglandins, thromboxanes and leucotrienes), and various cytokines (IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-8, TNF-α, GM-CSF, MIP-1a, MIP-1b, MIP-2 and IFN-γ).
The c-kit receptor can also be constitutively activated by mutations leading to abnormal cell proliferation and development of diseases such as mastocytosis (D816V mutation) and various cancers such as GIST (c-kitΔ27, a juxtamembrane deletion).
Furthermore, 60% to 70% of patients presenting with AML have blasts which express c-kit, the receptor for stem cell factor (SCF) (Broudy, 1997). SCF promotes growth of hematopoietic progenitors, and act as a survival factor for AML blasts. In some cases (1 to 2%) of AML, a mutation in a conserved residue of the kinase domain (Kit816) resulting in constitutive activation of c-kit has been described (Beghini et al., 2000; Longley et al., 2001). This gain of function mutation (Asp to Val/Tyr substitution) has been identified in mast cell leukemic cell lines and in samples derived from patients with mastocytosis (Longley et al., 1996).
In addition, we have studied about 300 patients afflicted with systemic mastocytosis and we have shown that the Kit816 mutation is expressed in about 60% of cases. In this regard, we filed WO 04/076693 which relates to tailored treatment of the different forms of mastocytosis depending on the presence or absence of the Kit816 mutation.
Thus, we recently have proposed to target c-kit to deplete the mast cells responsible for these disorders. We discovered in this regard, new potent and selective c-kit inhibitors which are 2-(3-aminoaryl)amino-4-aryl-thiazoles described in our PCT application WO 2004/014903.
The synthesis of substituted 2-aminothiazole is known from literature. In the following publications the general synthesis of these compounds are usually obtained using a two-stage scheme, including bromination of the initial ketones (A) (G. Crank and R. Kahn, Austr. J. Chem, 38(3), 447-458 (1985)) followed by cyclocondensation of the intermediate α-bromoketones (C) with thiourea (B) by refluxing in ethanol or methanol (M. Maziere et al, Bull. Soc. Chim. France, 1000-1003 (1963); J. D. Spivack U.S. Pat. No. 3,299,087).

However, when R is an electron withdrawing groups like nitro functionality, the yield of cycloaddition do not exceed 65% (S. P. Singh et al, Indian j. Chem. Sect. B, 29 (6), 531-538, (1990)). This disadvantage is probably due to the instability of the nitroarylthiourea, which leads to the formation of both impurity and highly reactive by-product, when reacting in the presence of a base.
It is apparent from the above, that this methodology applied to nitroarylthiourea has synthetic disadvantages concerning one or more of these characteristics: yield, scalability to multi-gram synthesis and purifications.